J. Braz. Chem. Soc. vol.25 número2

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Article

A

*e-mail: [email protected]

Direct, Rapid and Convenient Synthesis of Esters and Thioesters Using

PPh

₃

/

N

-Chlorobenzotriazole System

Hamed Rouhi-Saadabad and Batool Akhlaghinia*

Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran

Desenvolvemos um método eficiente de esterificação e tioesterificação de uma série de ácidos

carboxílicos com diferentes álcoois e tióis usando o reagente misto PPh3/N-clorobenzotriazol em

CH2Cl2 a temperatura ambiente.

We have developed an efficient method for esterification and thioesterification of various

carboxylic acids with different alcohols and thiols using PPh3/N-chlorobenzotriazole mixed reagent

in CH2Cl2 at room temperature.

Keywords: PPh3,N-chlorobenzotriazole (NCBT), esters, thioesters

Introduction

Esterification is the fundamental and routinely used functional group transformation in organic chemistry1_and

it is extensively employed for the protection and further manipulation of the carboxylic acid functional group as well as the synthesis of natural products. Traditionally, the simple condensation between a carboxylic acid and an alcohol is the most straightforward way to esterification. The difficulty stems primarily from the equilibration of the condensation reaction. The commonest approach to bias the equilibrium in favor of the product side is either by using the reactants in excess and/or continuously removing of the water formed during the reaction. The former treatment is not desirable in terms of “atom economy”2_{since the excess}

reactant remains to be separated from the reaction mixture. On the other hand, azeotropy is most frequently invoked, but a variety of dehydration methods have been put forth, although 100% conversion and, hence, 100% yield are, in general, not easy to achieve. Another problem emerges from the base or acid catalysts which are inevitably employed in this reaction. Under such conditions, the tolerance of a wide spectrum of functional groups that is often required in modern synthetic chemistry is not easy to achieve. Activation of the carboxylic acid or alcohol components with a stoichiometric amount of promoter such as carbodiimides,3

diethylazodicarboxylate,4_{5,5´-dimethyl-3,3’-azoisoxazole,}5

azopyridines,6_[{Cl(C

6F13C2H4)2SnOSn(C2H4C6F13)2Cl}2]

graphite bisulfate,7_{functionalized acidic ionic liquids,}8,9

TiO(acac)_2,10_{is another possible but uneconomical choice.}

These reactions historically faced purification challenges and often haunt the chemist in the isolation of the desired product. Development a new, simple, efficient, and highly profitable esterification method under mild reaction conditions and without tedious and difficult purification steps, is highly desirable and challenging.

The N-halo reagents in combination with PPh3 have

found widespread use in synthetic organic chemistry.11

In the present study, esterification and thioesterification of carboxylic acids were investigated by using

N-chlorobenzotriazole (NCBT, as an N-halo reagent) PPh₃ system. The reaction proceeds under mild, essentially neutral conditions and has been well documented for a variety of substrates.

Experimental

General

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spectrometer. The nuclear magnetic resonance (NMR) spectra were provided on Bruker Ultrashield Avance III 400 MHz instruments in CDCl3. Mass spectra were recorded

with a CH7A Varianmat Bremem instrument at 70 eV, in

m/z (rel%). NCBT was prepared and purified by the method described in the literature.12_{Preparation of benzyl benzoate}

by using PPh3/5,5’-dimethyl-3,3’-azoisoxazole, PPh3

/4,4’-azopyridine, Ph2PCl/I2/imidazole and PPh3/[bis(acetoxy)

iodo]benzene/diethylazodicarboxylate (DEAD) mixed reagents was performed according the methods reported previously.5,6,13,14

Preparation of benzyl benzoate by using PPh3/

trichloroisocyanuric acid (TCCA)

To a cold solution of PPh3 (0.327 g, 1.25 mmol) in

CH2Cl2 (3 mL), TCCA (0.0974 g, 0.42 mmol) was added

with continuous stirring. Benzoic acid (0.122 g, 1 mmol) was then added and stirring was continued for 15 min. Benzyl alcohol (0.270 g, 2.5 mmol) was added and the temperature was raised up to room temperature. The white suspension was neutralized by triethylamine (0.175 mL). Stirring was continued for 2.5 h at room temperature. The progress of the reaction was followed by TLC. Upon completion of the reaction, the concentrated residue was passed through a short silica-gel column using n-hexane–ethyl acetate (8:1) as eluent. Benzyl benzoate was obtained with 85% yield after removing the solvent under reduced pressure.

N-bromosuccinimide (NBS)

CH2Cl2 (3 mL), NBS (0.223 g, 1.25 mmol) was added with

continuous stirring. Benzoic acid (0.122 g, 1 mmol) was then added and stirring was continued for 15 min. Benzyl alcohol (0.270 g, 2.5 mmol) was added and the temperature was raised up to room temperature. The red suspension was neutralized by triethylamine (0.175 mL). Stirring was continued for 4.5 h at room temperature. The progress of the reaction was followed by TLC. Upon completion of the reaction, the concentrated residue was passed through a short silica-gel column using n-hexane–ethyl acetate (8:1) as eluent. Benzyl benzoate was obtained with 40% yield after removing the solvent under reduced pressure.

N-chlorosuccinimide (NCS)

CH2Cl2 (3 mL), NCS (0.166 g, 1.25 mmol) was added with

continuous stirring. Benzoic acid (0.122 g, 1 mmol) was then added and stirring was continued for 15 min. Benzyl alcohol (0.270 g, 2.5 mmol) was added and the temperature was raised up to room temperature. The pale yellow solution was neutralized by triethylamine (0.175 mL). Stirring was continued for 3 h at room temperature. The progress of the reaction was followed by TLC. Upon completion of the reaction, the concentrated residue was passed through a short silica-gel column using n-hexane–ethyl acetate (8:1) as eluent. Benzyl benzoate was obtained with 80% yield after removing the solvent under reduced pressure.

Preparation of benzyl benzoate by using PPh3/NCBT

To a cold solution of PPh3 (0.327 g, 1.25 mmol)

in CH2Cl2 (3 mL), freshly prepared NCBT (0.194 g,

1.25 mmol) was added with continuous stirring. Benzoic acid (0.122 g, 1 mmol) was then added and stirring was continued for 15 min. Benzyl alcohol (0.270 g, 2.5 mmol) was added and the temperature was raised up to room temperature. The pale yellow solution was neutralized by triethylamine (0.175 mL). Stirring was continued for 40 min at room temperature. The progress of the reaction was followed by TLC. Upon completion of the reaction, the concentrated residue was passed through a short silica-gel column using n-hexane–ethyl acetate (8:1) as eluent. Benzyl benzoate was obtained with 95% yield after removing the solvent under reduced pressure.

Benzyl benzoate (Table 3, entry 1)

m.p. 20-21°C (Lit. 19-21 °C);15 _{IR (neat)}_υ max/cm−1

3423, 3088, 3064, 3033, 2949, 2892, 1716 (C=O), 1601, 1585, 1451, 1376, 1314, 1270 (C–O), 1175, 1109, 1069, 710, 697; 1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ

8.14-8.11 (m, 2H, ArH), 7.62-7.58 (m, 1H, ArH), 7.51-7.41 (m, 7H, ArH), 5.41 (s, 2H, PhCH2).

Benzyl 4-methylbenzoate (Table 3, entry 2)

Solid; m.p. 45-46 °C (Lit. 45-46 °C);16_{IR (KBr)}_υ max/cm−1

3391, 3088, 3031, 2962, 2896, 1706 (C=O), 1609, 1454, 1370, 1267 (C–O), 1175, 1100, 751, 700; MS (EI) m/z 226 (M+_{, 10%), 118 (M}+_–PhCH

2O, 100%), 91 (PhCH2, 90%).

Benzyl 3,5-dimethylbenzoate (Table 3, entry 3)

Solid; m.p. 65-66 °C (Lit. 66-67 °C);17_{IR (KBr)}_υ max/cm−1

3423, 3063, 3033, 3009, 2951, 2918, 1717 (C=O), 1608, 1498, 1555, 1308, 1211 (C–O), 1115, 1010, 766, 754,

697; 1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ 7.73 (s,

2H, ArH), 7.50-7.48 (d, 2H, J 6.8 Hz, ArH) 7.45-7.36 (m,

3H, ArH), 7.22 (s, 1H, ArH), 5.39 (s, 2H, PhCH2), 2.39

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Benzyl 4-methoxybenzoate (Table 3, entry 4)

m.p. 24-26 °C (Lit. 25-27 °C);18_{IR (neat)}_υ max/cm

−1

3415, 3068, 2962, 2937, 2839, 1712(C=O), 1606, 1581, 1511, 1456, 1376, 1316, 1270, 1256 (C–O), 1167, 1099, 1029, 769, 696; 1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ

8.91 (td, 2H, J 9.2, 2.4 Hz, ArH), 7.49-7.46 (m, 2H, ArH), 7.44-7.29 (m, 3H, ArH), 6.97-6.93 (m, 2H, ArH), 5.37 (s, 2H, PhCH2), 3.89 (s, 3H, OCH3).

Benzyl 2-chlorobenzoate (Table 3, entry 5)

m.p. 18-20 °C; IR (neat) υ_max/cm−1_{3064, 3027, 2925,}

2847, 1722 (Lit. 1729, C=O),19_{1589, 1484, 1451, 1378,}

1290 (C–O), 1131, 1046, 936, 751, 740.

Benzyl 4-chlorobenzoate (Table 3, entry 6)

m.p. 25-26 °C (Lit. 25-26 °C);16_{IR (neat)} _υ max/cm

−1

3431, 3064, 3035, 2949, 1721 (C=O), 1594, 1487, 1400, 1270 (C–O), 1114, 1092, 1014, 758, 696.

Benzyl 4-bromobenzoate (Table 3, entry 7)

Solid; m.p. 51-52 °C (Lit. 52-53 °C);16 _{IR (KBr)}

υ

max/cm

−1_{3415, 3072, 3039, 2974, 2892, 1715 (C=O),}

1588, 1455, 1396, 1269 (C–O), 1169, 1089, 1008, 759,

698; 1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ 7.97 (d,

2H, J 8.4 Hz, ArH), 7.61 (d, 2H, J 8.4 Hz, ArH), 7.49-7.38 (m, 5H, ArH), 5.40 (s, 2H, PhCH2); MS (EI) m/z 291 (M

+_,

5%), 182 (M+_–PhCH

2O, 87%), 91 (PhCH2, 87%).

Benzyl 3,4-dichlorobenzoate (Table 3, entry 8)

Solid; m.p. 57-58 °C (Lit. 58-60 °C);16_{IR (KBr)}

υ_max/cm−1_{3092, 3072, 3039, 2953, 2892, 1724 (C=O), 1585,}

1564, 1458, 1379, 1273 (C–O), 1236, 1106, 1032, 757,

696; 1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ 8.16 (d,

1H, J 2 Hz, ArH), 7.91 (dd,1H, J 8.4, 2 Hz, ArH), 7.53 (d, 1H, J 8.4 Hz, ArH), 7.48-7.39 (m, 5H, ArH), 5.39 (s, 2H, PhCH2); MS (EI) m/z 284 (M+4, 5%), 282 (M+2, 26%), 280

(M+_{, 32%), 245 (M}+_{–Cl, 38%), 173 (M}+_–PhCH

2O, 100%)

145 (M+_–PhCl

2, 35%), 91(PhCH2, 100%).

Benzyl 4-nitrobenzoate (Table 3, entry 9)

Solid; m.p. 82-83 °C (Lit. 82-83°C);16 _{IR (KBr)}

υ

max/cm

−1_{3112, 3051, 1712 (C=O), 1604, 1522, 1347, 1277}

(C–O), 1121, 1104, 744, 715.695; 1_{H NMR (400 MHz,}

CDCl3, 25 °C, ppm) δ 8.32-8.25 (m, 4H, ArH), 8.50-8.40

(m, 5H, ArH), 5.44 (s, 2H, PhCH2); MS (EI) m/z 257 (M+,

10%), 150 (M+_–PhCH

2O, 100%), 91 (M

+_–PhCH

2, 100%).

Benzyl 3-nitrobenzoate (Table 3, entry 10)

υ

max/cm

−1_{3436, 3084, 3039, 2962, 2872, 1727 (C=O), 1613,}

1531, 1350, 1293, 1258 (C–O), 1130, 1070, 717, 697;

1_{H NMR (400 MHz, CDCl}

3, 25 °C, ppm) δ 8.91 (s, 1H,

ArH), 8.45-8.41 (m, 2H, ArH), 7.68 (t, 1H, J 8 Hz, ArH), 7.51-7.29 (m, 5H, ArH), 5.45 (s. 2H, PhCH2).

Benzyl cinnamate (Table 3, entry 11)

υ_max/cm−1_{3064, 3027, 2966, 2896, 1711 (C=O), 1636,}

1310, 1162 (C–O), 980, 767, 697; MS (EI) m/z 238 (M+_,

10%), 130 (M+_–PhCH

2O, 100%), 103 (PhCH2O, 90%), 91

(PhCH2, 90%).

(E)-Benzyl 3-(4-chlorophenyl)acrylate (Table 3, entry 12)

Solid; m.p. 122-124 °C;IR (KBr)υ_max/cm−1_{3064, 3027,}

2953, 1708 (Lit. 1709, C=O),22_{1637, 1488, 1309, 1166}

(C–O), 988, 820, 695; 1_{H NMR (400 MHz, CDCl}

3, 25 °C,

ppm) δ_{7.70 (d, 1H,} J 16 Hz, PhCH=CH–), 7.49-7.29 (m,

9H, ArH), 6.49 (d, 1H, J 16 Hz, PhCH=CH–), 5.29 (s, 2H, PhCH2); MS (EI) m/z 274 (M+2, 10%) 272 (M

+_{, 35%), 164}

(M+_–PhCH

2O), 91 (M+–PhCH2, 100%).

(E)-Benzyl 3-(3-nitrophenyl)acrylate (Table 3, entry 13)

υ_max/cm−1_{3072, 2925, 1711 (C=O), 1641, 1526, 1351, 1176}

(C–O), 1008, 730; MS (EI) m/z 282 (M+_{, 10%), 175 (M}+_–

PhCH2O, 81%), 103 (PhCH2O, 80%) 91 (PhCH2, 100%).

Benzyl 2-phenylacetate (Table 3, entry 14)

Solid; m.p. 51-52 °C (Lit. 52 °C);23 _{IR (KBr)}

υ_max/cm−1_{3084, 3060, 3031, 2953, 1737 (C=O), 1496, 1454,}

1380, 1260 (C–O), 1145, 749, 695; 1_{H NMR (400 MHz,}

CDCl3, 25 °C, ppm) δ 7.41-7.29 (m, 10H, ArH), 5.17 (s,

2H, PhCH2–O), 3.71 (s, 2H, PhCH2–CO).

Benzyl 2,2-diphenylacetate (Table 3, entry 15)

m.p. 34-35 °C (Lit. 35 °C);24 _{IR (neat)} _υ max/cm−1

3084, 3063, 3030, 2953, 1736 (C=O), 1600, 1496, 1453, 1184, 1144 (C–O), 1004, 975, 744, 696; MS (EI) m/z 193 (M+₋_PhCH

2O, 30%), 166 ((Ph)2CH, 100%), 91 (PhCH2,

80%).

Benzyl 2-(4-methoxyphenyl)acetate (Table 3, entry 16)

υ_max/cm−1_{3063, 3035, 2957, 2839, 1713 (C=O), 1606, 1511,}

1455, 1315, 1257 (C–O), 1167, 1100, 1028, 768, 750, 796; MS (EI) m/z 256 (M+_{, 5%), 164 (M}+_–PhCH

2, 20%), 149

(M+_–PhCH

2O, 80%), 91 (PhCH2, 80%).

Benzyl stearate (Table 3, entry 17)

Solid; m.p. 44-45°C (Lit. 44-45 °C);26 _{IR (KBr)}

υ

max/cm

−1_{3092, 2955, 2917, 2849, 1743 (C=O), 1471, 1393,}

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Benzyl thiophene-3-carboxylate (Table 3, entry 18)

Solid; m.p. 139-141°C (Lit. 140-142 °C);27_{IR (KBr)}

υ_max/cm−1_{3111, 3035, 1716 (C=O), 1522, 1407, 1261}

(C–O), 1187, 1100, 747; 1_{H NMR (400 MHz, CDCl} 3, 25 °C,

ppm) δ 8.18-8.17 (m, 1H, ArH), 7.60-7.58 (m, 1H, ArH), 7.48-7.33 (m, 6H ArH), 5.36 (s, 2H, PhCH2).

Phenethyl 4-nitrobenzoate (Table 3, entry 19)

υ

max/cm

−1_{3068, 1710 (C=O), 1597, 1486, 1450, 1379,}

1362, 1287 (C–O), 1051, 940, 750, 695; MS (EI) m/z 164 (M+_–PhCH

2CH2, 17%), 149 (4-NO2PhCO, 80%), 104

(PhCH2CH2, 100%), 91 (PhCH2, 80%).

3-Phenylpropyl 4-nitrobenzoate (Table 3, entry 20):

υ_max/cm−1_{3120, 2958, 1716 (C=O), 1602, 1523, 1352,}

1286 (C–O), 1103, 870, 746, 717, 700; MS (EI) m/z 284 (M+_{, 5%), 149 (4-NO}

2PhCO, 60%), 118 (PhCH2CH2CH2,

100%), 91 (PhCH2, 90%).

Butyl 4-nitrobenzoate (Table 3, entry 21)

m.p. 33-34 °C (Lit. 34-35 °C);30_{IR (neat)} _υ max/cm−1

3117, 3080, 3060, 2963, 2938, 2868, 1717 (C=O), 1606, 1526, 1352, 1278 (C–O), 1103, 872, 846, 786, 714;

3, 25 °C, ppm) δ 8.30 (d, 2H,

J 8.8 Hz,ArH), 8.22 (d, 2H, J 8.8 Hz,ArH), 4.39 (t, 2H,

J 6.8 Hz,OCH2CH2), 1.83-1.76 (m, 2H, OCH2CH2),

1.55-1.46 (m, 2H, CH2CH3), 1.01 (t, 3H, J 7.2 Hz,OCH2CH3).

1-Phenylethyl 4-nitrobenzoate (Table 3, entry 22)

υ_max/cm−1_{3113, 3039, 2978, 2933, 1723 (C=O), 1607, 1528,}

1454, 1351, 1271 (C–O), 1102, 1060, 1014, 873, 841, 719;

3, 25 °C, ppm) δ 8.32-8.29 (m, 2H,

ArH), 8.27-8.24 (m, 2H, ArH), 7.49-7.34 (m, 5H, ArH), 6.18 (q, 1H, J 6.4 Hz,OCH(Ph)CH3), 1.74 (d, 3H, J 6.4 Hz,OCHCH3).

Benzhydryl 4-nitrobenzoate (Table 3, entry 23)

υ_max/cm−1_{3109, 3051, 2859, 1721 (C=O), 1609, 1525, 1446,}

1345, 1280 (C–O), 1261, 1116, 1103, 967, 763, 719, 699;

3, 25 °C, ppm) δ 8.33 (s, 4H,

ArH), 8.47-8.35 (m, 10H, ArH), 7.17 (s, 1H, Ph2CH); MS

(EI) m/z 333 (M+_{, 10%), 182 (M}+_{–2Ph, 88%) 165 (M}+_–

NO2PhCO2, 100%) 151 (M +_–Ph

2CHO, 72%).

Cyclohexyl 4-nitrobenzoate (Table 3, entry 24)

υ

max/cm

−1_{2117, 2938, 2860, 1720 (C=O), 1609, 1528, 1454,}

1348, 1319, 1278 (C–O), 1115, 1013, 835, 719; MS (EI)

m/z 168 (M+_{–cyclohexyl, 45%), 149 (4-NO}

2PhCO, 60%),

104 (PhCO, 100%), 82 (cyclohexyl, 90%).

Phenyl 4-nitrobenzoate (Table 3, entry 26)

υ

max/cm

−1_{3113, 1741 (C=O), 1609, 1520, 1484, 1348, 1269}

(C–O), 1183, 1079, 1017, 847; 1_{H NMR (400 MHz, CDCl} 3,

25 °C, ppm) δ_{8.41 (dd, 2H,} J 6.4, 2.8 Hz, ArH), 8.38 (dd, 2H, J 6.4, 2.8 Hz, ArH), 7.50-7.46 (m, 2H ArH), 7.36-7.33 (m, 1H, ArH), 7.28-7.24 (m, 2H, ArH).

m-Tolyl 4-nitrobenzoate (Table 3, entry 27)

Solid; m.p. 86-87 °C (Lit. 87 °C);35_{IR (KBr)}_υ max/cm−1

3109, 3080, 2985, 2921, 2850, 1736 (C=O), 1607, 1529, 1487, 1352, 1273 (C–O), 1236, 715; MS (EI) m/z 257 (M+_,

5%), 149 (M+_–(_m_{-MePhO)), 103 (}_m_{-MePhO, 62%).}

4-Chlorophenyl 4-methoxybenzoate (Table 3, entry 28)

υ

max/cm

−1_{3015, 2982, 2847, 1727 (C=O), 1610, 1515, 1489,}

1267 (C–O), 1204, 1167, 1072, 1021, 842, 761; 1_{H NMR}

(400 MHz, CDCl3, 25 °C, ppm) δ 8.16 (dd, 2H, J 6.8, 2 Hz,

ArH), 7.41 (dd, 2H, J 6.8,2Hz, ArH), 7.17 (dd, 2H, J 6.8, 2 Hz,

ArH), 1.48 (dd, 2H, J 7.2, 2 Hz, ArH), 3.92 (s, 3H, OCH3).

Phenyl stearate (Table 3, entry 29)

υ

max/cm

−1_{2954, 2917, 2849, 1743 (C=O), 1741, 1393}

(C–O), 961, 754.

S-Cyclohexyl 3,5-dimethylbenzothioate (Table 3, entry 30)

υ_max/cm−1_{2929, 2853, 1659 (O=C–S), 1606, 1448, 1292,}

1149, 1034, 697, 861, 786, 703; 1_{H NMR (400 MHz,}

CDCl3, 25 °C, ppm) δ 7.58 (s, 2H, ArH), 7.20 (s, 1H, ArH),

3.73 (t, 1H, J 4 Hz, SCH–), 2.37 (s, 6H, 2CH3), 2.05-1.27

(m, 10H, CH2 cyclohexyl ring).

S-Octyl 4-methoxybenzothioate (Table 3, entry 31)

m.p. 24-26 °C (Lit. 25-27 °C);38_{IR (neat)}_υ max/cm

−1_3011,

2955, 2926, 2854, 1655 (O=C–S), 1602, 1578, 1508, 1462, 1315, 1259, 1213, 1167, 1031, 913; 1_{H NMR (400 MHz,}

CDCl3, 25 °C, ppm) δ 7.97 (d, 2H, J 8.8 Hz, ArH), 6.93 (d,

2H, J 8.8 Hz, ArH), 3.06 (t, 2H, J 7.6 Hz, S–CH2), 1.71-1.60

(m, 2H, CH2), 1.43 (q, 2H, J 6.8 Hz, R−CH2CH3), 1.32-1.29

(m, 8H, 4CH2), 0.89 (t, 3H, J 6.8 Hz, R–CH2CH3).

(E)-S-Cyclohexyl 3-(3-nitrophenyl)prop-2-enethioate (Table 3, entry 32)

Solid; m.p. 141-143 °C (Lit.142-145 °C);39_{IR (KBr)}

(5)

1050, 997, 736, 702; MS (EI) m/z 291 (M+_{, 5%), 175}

(M+_{–cyclohexyl–S, 100%), 115 (cyclohexyl–S, 80%), 82}

(cyclohexyl, 100%).

S-Octyl 4-nitrobenzothioate (Table 3, entry 33)

m.p. 27-29 °C (Lit. 28-30 °C);39_{IR (neat)} _υ max/cm

−1

3105, 2953, 2927, 2855, 1666 (O=C–S), 1605, 1528, 1349, 1202, 923, 848.

S-Benzyl 4-nitrobenzothioate (Table 3, entry 34)

Solid; m.p. 85-86 °C (Lit. 85.4-86.5 °C);40_{IR (KBr)}

υ

max/cm

−1_{3113, 1643 (O=C–S), 1601 1521, 1349, 1318,}

1203, 1193, 930, 850, 711, 691; 1_{H NMR (400 MHz,}

CDCl3, 25 °C, ppm) δ 8.32 (dd, 2H, J 7.2, 2 Hz, ArH),

8.14 (dd, 2H, J 7.2, 2 Hz, ArH), 7.42-7.28 (m, 5H, ArH), 4.39 (s, 2H, PhCH2).

S-Cyclohexyl 4-nitrobenzothioate (Table 3, entry 35)

Solid; m.p. 139-140 °C;IR (KBr)υ_max/cm−1_3109,_2942,

2928, 2851, 1655 (O=C–S), 1604, 1523, 1349, 1318, 1195, 1174, 1109, 922, 885, 848, 690; 1_{H NMR}6_{(400 MHz,}

CDCl3, 25 °C, ppm) δ 8.32-8.29 (m, 2H, ArH), 8.13-8.10

(m, 2H, ArH), 3.82-3.76 (m, 1H, SCH–), 2.06-1.48 (m, 10H, CH2 cyclohexyl ring).

S-Benzyl 2,2-diphenylethanethioate (Table 3, entry 36)

υ

max/cm

−1_{3333, 3088, 3064, 3027, 2917, 2843, 1680}

(O=C–S), 1494, 1453, 1011, 994, 741, 698; MS (EI) m/z

317 (M+_{, 5%), 196 (M}+_–PhCH

2S, 10%), 166 ((Ph)2CH,

100%), 91 (PhCH2, 90%).

S-p-Tolyl benzothioate (Table 3, entry 37)

Solid; m.p. 75-77 °C (Lit. 76.5-77 °C);42_{IR (KBr)}_υ max/cm

−1

3047, 2917, 2847, 1668 (O=C–S), 1482, 1450, 1274, 1203, 1169, 897, 808, 773, 689; MS (EI) m/z 228 (M+_{, 10%), 122}

(M+_–_p-_{MePhS, 80%), 105 (PhCO, 100%), 91 (PhCH} 2, 90%).

S-p-Tolyl 2,2-diphenylethanethioate (Table 3, entry 38)

Solid; m.p. 96-98 °C (Lit. 98 °C);43_{IR (KBr)}_υ max/cm

−1

3084, 3059, 3027, 2917, 2843, 1674 (O=C–S), 1482, 1451, 981, 741, 698; MS (EI) m/z 316 (M+_{, 3%), 193 (M}+

–4-MePhS, 60%), 166 ((Ph)2CH, 100%), 90 (PhCH2, 80%).

Results and Discussion

In continuation of our study to extend the scope of N-halo reagents in conjunction with PPh3,

11,44_we

investigated the applicability of PPh3/trichloroisocyanuric

acid (TCCA), PPh3/N-bromosuccinimide (NBS),

PPh3/N-chlorosuccinimide (NCS) and PPh3/(NCBT)

systems in direct esterification reaction of benzoic acid with benzyl alcohol (Table 1, entries 1-3 and 8). Recently, direct esterification reaction was also reported by using PPh3 and an electron deficient reagent such as PPh3

/5,5’-dimethyl-3,3’-azoisoxazole,5_PPh

3/4,4’-azopyridine, 6

Ph2PCl/I2/imidazole13 and PPh3/[bis(acetoxy)iodo]benzene/

diethylazodicarboxylate (DEAD)14_{(Table 1, entries 4-7).}

As is apparent from Table 1, PPh3/(NCBT) mixed reagent

is the most efficient mixed-reagent system, for conversion of benzoic acid to benzyl benzoate. Replacement of NCBT by every above-mentioned mixed reagent systems produces benzyl benzoate in longer reaction time.

According the data from Table 1,PPh3/NCBT system

is the best choice for direct esterification of benzoic acid (Scheme 1).

To achieve high reaction efficiency, the reaction of benzoic acid with benzyl alcohol was chosen as model reaction to investigate the applicability of PPh3/NCBT

system in direct esterification and thioesterification reactions of carboxylic acids. The effects of different molar ratios of PPh3/NCBT/RCO2H/ROH in various solvents were

examined on the model reaction.

Treating a solution of PPh3 (1 equiv.) and NCBT

(1 equiv.) in CH3CN at room temperature with different

Table 1. Esterification of benzoic acid with benzyl alcohol by using different mixed reagent systema

entry Mixed reagents Reaction condition time / h Isolated yield / %

1 PPh₃/trichloroisocyanuric acid (TCCA) CH₂Cl₂/r.t.b _2.5 ₈₅

2 PPh3/N-bromosuccinimide (NBS) CH2Cl2/r.t.b 4.5 40

3 PPh₃/N-chlorosuccinimide (NCS) CH₂Cl₂/r.t.b ₃ ₈₀

45 _PPh

3/5,5’-dimethyl-3,3’-azoisoxazole CH3CN/reflux 6.5 89

56 _PPh

3/4,4’-azopyridine CH3CN/reflux 3 86

613 _Ph

2PCl, I2, imidazole CH3CN/reflux 4 91

714,c _PPh

3/[bis(acetoxy)iodo]benzene/diethylazodicarboxylate (DEAD) THF/r.t.b 16 76

8 PPh₃/N-chlorobenzotriazole (NCBT) CH₂Cl₂/r.t.b _{40 min} ₉₅

a_{The experimental details are shown in experimental section;}b_{r.t.: room temperature;}c_{the result corresponds to the esterification reaction of}_p_{-nitrobenzoic}

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molar ratios of benzoic acid and benzyl alcohol afforded benzyl benzoate in high yield over 2-5 h (Table 2, entries 1-4). Increasing the molar ratios of PPh3/NCBT and benzyl

alcohol in CH3CN gave 100% conversion of benzoic acid

to benzyl benzoate in 40 min (Table 2, entries 5-6). As the applying 1.25/1.25/1/2.5 molar ratios of PPh3/NCBT/

RCO2H/ROH in CH3CN gave 100% conversion of benzoic

acid to benzyl benzoate in 40 min, esterification reaction was examined in CH2Cl2 at the same conditions. Surprisingly,

there is no difference between the rate of esterification reaction in CH3CN and CH2Cl2 (Table 2, compare entries

5 and 7). At the same conditions performing the reaction in other solvents such as THF, CHCl3, 1,4-dioxane, acetone,

toluene and hexane produced the desired product with lower yield and in longer reaction time (Table 2, entries 8-13). The best result was obtained by applying 1.25/1.25/1/2.5 molar ratios of PPh3/NCBT/ RCO2H/ROH in CH3CN and

CH2Cl2. Because of economic consideration CH2Cl2 was

chosen for further experiments. To investigate the chemical activities of PPh3 and NCBT in the esterification reaction,

the model reaction was carried out in the absence of PPh3

and NCBT respectively. As summarized in Table 2, no desired product was detected in the absence of PPh3 and

NCBT (Table 2, entries 14-15).

To explore the generality and scope of the esterification and thioesterification reaction by using PPh3/NCBT mixed

reagent, the optimized reaction conditions 1.25/1.25/1/2.5

molar ratio of PPh3/NCBT/RCO2H/ROH or RSH in

CH2Cl2 were used for the synthesis of a series of esters

and thioesters (Table 3). According to the results obtained (Table 3) esters and thioesters were prepared from the reaction of aromatic and aliphatic carboxylic acids with primary and secondary aliphatic and benzylic alcohols, phenols and aliphatic and aromatic thiols by using PPh3/NCBT system in high isolated yields.

The aromatic carboxylic acids with electron-withdrawing substituents were rapidly reacted with benzyl alcohol and converted into their corresponding esters in a very short reaction time (20-35 min) with 100% conversion (Table 3, entries 6-10). In spite of inductive effect of chlorine which caused o-chlorobenzoic acid (pKa = 2.89)

stronger acid than p-chlorobenzoic acid (pK_a = 4.03),

o-chlorobenzoic acid was converted to the corresponding ester in longer reaction time than p-chlorobenzoic acid (e.g., compare entry 5 with 6). Difference in reactivity between o-chlorobenzoic acid and p-chlorobenzoic acid can be rationalized by the steric effect of chlorine in

Scheme 1.

Table 2. Conversion of benzoic acid to benzyl benzoate with PPh3/NCBT/

benzyl alcohol system under different reaction conditions

entry Solvent

Molar Ratio PPh₃/NCBT/ RCO₂H/ROH

time / min Isolated yield / %

1 CH₃CN 1/1/1/1 5 h 80

2 CH₃CN 1/1/1/1.5 3 h 85

3 CH3CN 1/1/1/2 2 h 90

4 CH₃CN 1/1/1/2.5 2 h 92

5 CH₃CN 1.25/1.25/1/2.5 40 95

6 CH3CN 1.25/1.25/1/3.125 40 95

7 CH₂Cl₂ 1.25/1.25/1/2.5 40 95

8 THF 1.25/1.25/1/2.5 100 80

9 CHCl₃ 1.25/1.25/1/2.5 80 90

10 1,4-dioxane 1.25/1.25/1/2.5 90 65

11 acetone 1.25/1.25/1/2.5 70 75

12 toluene 1.25/1.25/1/2.5 60 72

13 hexane 1.25/1.25/1/2.5 90 55

14 CH₂Cl₂ 0/1.25/1/2.5 90 0

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ortho position of aromatic ring. The reaction of aromatic carboxylic acids bearing electron-donating substituents, with benzyl alcohol was completed in longer reaction time (55-70 min) than the above-mentioned acids (e.g., compare entries 2-4 with 6-10). By now, we can conclude that the electron deficiency in carbonyl group plays an important role in the reaction rate of esterification. This effect has been observed in the esterification reaction of cinnanic acid and substituted cinnamic acids (e.g., compare entries 11 with 12-13). PPh3/NCBT system converted

aliphatic carboxylic acids to the corresponding esters in a more longer reaction time (Table 3, entries 14-17). In comparison, primary aliphatic alcohols have low reactivity than primary benzylic ones towards p-nitro benzoic acid (Table 3, entries 19-21). Also, secondary alcohols have little reactivity than primary alcohols in the presence of PPh3/NCBT system (Table 3, entries 22-24). As is to be

expected, tertiary alcohols because of steric hindrance

were resistant to react with carboxylic acids by using the above-mentioned mixed reagent (Table 3, entry 25). As far as we know, none of the reported methods on esterification reaction by using PPh3/5,5’-dimethyl-3,3’-azoisoxazole,

5

PPh3/4,4’-azopyridine,6 Ph2PCl/I2/imidazole13 and

PPh3/[bis(acetoxy)iodo]benzene/diethylazodicarboxylate

(DEAD)14_{have shown any reactivity from tertiary alcohols}

towards benzoic acids. In order to gain more insight into the general applicability of this method, we also studied the possibility of applying PPh3/NCBT system to the reaction

of carboxylic acids with phenols. On the basis of the results obtained from Table 3, aromatic and aliphatic carboxylic acids react smoothly with phenols, and the corresponding esters are produced with high yields (Table 3, entries 26-29). This mixed reagent system also converts aliphatic and aromatic carboxylic acids to the corresponding thioesters with primary and secondary aliphatic and aromatic thiols (Table 3, entries 30-38).

Table 3. Conversion of different carboxylic acids to different esters and thioesters by using PPh₃/NCBT/alcohol (or phenol or thiol) system

entry Carboxylic acid Alcohol/phenol/ thiol Producta _{time / min} _{Yield / %}

1 benzyl alcohol 40 95

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Table 3. continuation

19 2-phenyl ethanol 50 90

20 3-phenyl-1-propanol 90 90

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22 1-phenyl ethanol 130 85

23 benzhydrol 180 70

24 cyclohexanol 100 92

25 1-adamantanol 24 h trace

26 phenol 90 90

27 m-cresol 95 90

28 p-chlorophenol 100 95

29 phenol 150 87

30 cyclohexanthiol 90 85

31 1-octanthiol 120 90

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34 benzyl mercaptan 40 95

36 benzyl mercaptan 120 80

37 p-methyl thiophenol 90 85

38 p-methyl thiophenol 200 80

a_{All the products were identified by comparing their spectral data with those of an authentic sample.}

In our experiments, the completion of the reaction was confirmed by the disappearance of the carboxylic acids on TLC followed by the disappearance of acidic OH stretching frequency at 3400-2400 cm-1_{in FTIR spectra.}

Also, absorption bands at 1743-1706 and 1393-1144 cm-1

due to carbonyl and C–O group of esters in FTIR spectra confirmed the ester formation. Formation of thioesters was also confirmed by appearance of an absorption bands at 1681-1643 cm-1_{due to carbonyl group (O=C–S) of}

thioesters. All of the products were known compounds and characterized by the IR and comparison of their melting points with known compounds. The structure of selected products was further confirmed by 1_{H NMR spectroscopy}

and mass spectrometry.

Conclusion

In this study, we introduced the application of NCBT (as an N-halo reagent) in conjunction with PPh3 for esterification

and thioesterification reactions. In comparison with the previously reported methods, the present protocol offers several advantages: (i) the reaction proceeds smoothly with a wide range of carboxylic acids (aromatic and aliphatic) and alcohols /or phenols and thiols. (ii) the reagents (PPh3

and NCBT) offers easy handling and simple work-up; (iii) this method has satisfactory yields of a variety of esters and

thioesters; (iv) in contrast to the previously reported systems, which proceeded by dehydration reaction between carboxylic acids and alcohols, in the present method, esters are produced in a short reaction time. (v) PPh3 and NCBT system could

be considered as an attractive and useful contribution to the present organic synthesis for direct esterification and thioesterification of different carboxylic acids.

Supplementary Information

Supplementary information is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgement

The authors gratefully acknowledge the partial support of this study by Ferdowsi University of Mashhad Research Council (Grant no. p/3/19312).

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Submitted: September 6, 2013